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Alex_Krycek

COVID-19 antivirals and vaccines (Megathread)

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There have been some promising developments regarding Chloroquine (a generic anti-malarial)  as a potential treatment for COVID-19.  South Korea has apparently begun incorporating it into their treatment regimens, with positive results.  Chloroquine (chloroquine diphosphate) allows Zinc to permeate the cell membrane and inhibit the replication of the virus.   

Here is the full breakdown with citations:  https://www.youtube.com/watch?v=U7F1cnWup9M

 

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15 minutes ago, Alex_Krycek said:

Chloroquine (chloroquine diphosphate) allows Zinc to permeate the cell membrane and inhibit the replication of the virus.   

So the paper discussing the use of cholorquine (and Remdesivir) is authored by Wang et al. (Cell Research volume 30, pages269–271 2020). The mechanism is not actually known but based on other viral data it is suspected to work by increasing the endosomal pH and interfering with glycosylation. The authors also speculate that modulating the immune system may also play a factor. 

Edit: apparently some studies with SARS suggest a role of zinc in inhibition, but from the looks of it most are in vitro data and I am not sure whether there are more studies out there.

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M.S. Shukor1 and M.Y. Shukor2
 
1Snoc International Sdn Bhd, Lot 343, Jalan 7/16 Kawasan Perindustrian Nilai 7, Inland Port, 71800,  Negeri Sembilan, Malaysia.
2Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, UPM 43400 Serdang, Selangor, Malaysia.
 
 
Covid-19 is now a pandemic affecting humans at a global scale. Researchers are still trying to find a cure and the vaccine to fight this disease. Drug-based cure and vaccine are overwhelmingly virus-specific and newer drugs and vaccines are needed to resist new novel viral infections. A shift towards herbal remedies to fight viral infections is an approach that can be explored especially in poorer countries or when drugs and vaccines are still not available. One of the top herbal remedies that emerges as a prime weapon for viral infection is Carica papaya, where the leaves extract has been tested in clinical environment in patients infected by the dengue virus. In two studies, platelets, white blood cells and neutrophils counts were back to normal after the administration of papaya leaves aqueous extract and the infected patients recovered (Ahmad et al. 2011; Kumar et al. 2015). Further research has demonstrated that papaya leaf extract decrease dengue complication through another route by inhibiting viral production. A study suggests that papaya leaves extract significantly cause the expression of NS1 and envelope proteins to be lowered in DENV-infected THP-1 cells. A significant lowering of the intracellular viral load supports papaya leaves extract antiviral activity (Sharma et al. 2019). In addition, papaya extracts and papaya-associated phytochemicals possibly enhance recovery in dengue infected patients through their anti-inflammatory and immunomodulatory properties (Pandey et al. 2016). A study shows that nine selected ligands from Carica papaya leaves show good binding to viral proteins from dengue, influenza A (H1N9) and chikungunya (Narayanaswamy et al. 2017).
 
As more and more wonderful properties of papaya leaves extract are reported in the literature, researchers began to use the extracted phytochemicals from the plant to combat other viral infections either in vivo, in vitro or in silico. SARS-CoV-2 is the novel virus that causes Covid-19. It has not benefit from the usage of papaya extract to fight its infection, not yet, but there is a growing body of evidences that suggest its probable usage to combat Covid-19. For a start, the anti-inflammatory and immunomodulatory properties of papaya leaves extract can increase an infected person chance of recovering from the infection. The papaya leaves extract is able to reduce the severity of cytokine storm in dengue infection in mice model (Norahmad et al. 2019). Cytokine storm is one of the most important mechanisms that lead to deaths of Covid-19-infected patients (Chen et al. 2020). Cytokine storm occurs when the lungs of infected patients become severely inflamed due to the massive overproduction of a host of mediators such as interleukins, interferons, tumour necrosis factor, macrophage and other factors which are lumped together as cytokines or chemokines. Cytokine storms often lead to infected cells dying through apoptosis and necrosis leading to severe tissue damage and haemorrhages triggering multiple organ failure (Tetro 2020; Chen et al. 2020; Yao et al. 2020).
 
In another study, patients having virus-induced lung damage were given fermented papaya preparation for one month. The researchers observed an increase in salivary IgA and increase in phase II and SOD enzyme expression levels, which are essential antioxidants in the respiratory tract (Marotta et al. 2012). Consumption of papain leaf extract can probably help in fighting Covid-19 infection, but more studies are needed to support this premise. An important step for a start is the in silico docking behavior of potential ligands from papaya leaves extract to the papain-like Covid-19 protease; one of the main targets of Covid-19 antiviral drug screening strategy (Arya et al. 2020; Zhang et al. 2020). 
 
Reference
 
Ahmad N, Fazal H, Ayaz M, Abbasi BH, Mohammad I, Fazal L (2011) Dengue fever treatment with Carica papaya leaves extracts. Asian Pacific Journal of Tropical Biomedicine 1, 330–333. doi:10.1016/S2221-1691(11)60055-5.
Arya R, Das A, Prashar V, Kumar M (2020) Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs. doi:10.26434/chemrxiv.11860011.v2.
Chen C, Zhang XR, Ju ZY, He WF (2020) [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies]. Zhonghua Shao Shang Za Zhi = Zhonghua Shaoshang Zazhi = Chinese Journal of Burns 36, E005. doi:10.3760/cma.j.cn501120-20200224-00088.
Kumar DrCVMN, Vadlamudi T, Venkatamuni A, Vardhan V, Prasad Y, Ravi U, D.V.R. S (2015) Therapeutic potential of Carica papaya l. leaf extract in treatment of dengue patients. International Journal of Applied Biology and Pharmaceutical Technology 6, 93–98.
Marotta F, Naito Y, Jain S, Lorenzetti A, Soresi V, Kumari A, Carrera Bastos P, Tomella C, Yadav H (2012) Is there a potential application of a fermented nutraceutical in acute respiratory illnesses? An in-vivo placebo-controlled, cross-over clinical study in different age groups of healthy subjects. Journal of Biological Regulators and Homeostatic Agents 26, 285–294.
Narayanaswamy R, KW L, ME N (2017) Molecular docking analysis of Carica papaya Linn constituents as antiviral agent. International Food Research Journal 24, 1819–1825.
Norahmad NA, Mohd Abd Razak MR, Mohmad Misnan N, Md Jelas NH, Sastu UR, Muhammad A, Ho TCD, Jusoh B, Zolkifli NA, Thayan R, Mat Ripen A, Zainol M, Syed Mohamed AF (2019) Effect of freeze-dried Carica papaya leaf juice on inflammatory cytokines production during dengue virus infection in AG129 mice. BMC Complementary and Alternative Medicine 19,. doi:10.1186/s12906-019-2438-3.
Pandey S, Cabot PJ, Shaw PN, Hewavitharana AK (2016) Anti-inflammatory and immunomodulatory properties of Carica papaya. Journal of Immunotoxicology 13, 590–602. doi:10.3109/1547691X.2016.1149528.
Sharma N, Mishra KP, Chanda S, Bhardwaj V, Tanwar H, Ganju L, Kumar B, Singh SB (2019) Evaluation of anti-dengue activity of Carica papaya aqueous leaf extract and its role in platelet augmentation. Archives of Virology 164, 1095–1110. doi:10.1007/s00705-019-04179-z.
Tetro JA (2020) Is COVID-19 receiving ADE from other coronaviruses? Microbes and Infection. doi:10.1016/j.micinf.2020.02.006.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D (2020) In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. doi:10.1093/cid/ciaa237.
Zhang D, Wu K, Zhang X, Deng S, Peng B (2020) In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. Journal of Integrative Medicine 18, 152–158. doi:10.1016/j.joim.2020.02.005.

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Think the evidence is a bit weak to support "  Consumption of papain leaf extract can probably help in fighting Covid-19 infection..."

Ahmad (2011)  rported in a pretty obscure journal treatment of a single patient observed minor CBC changes and "patient feelings" and Kumar et al (2015) reported statistically significant but minor CBC changes and observed treated patients (there was no apparent control group) "started to recover".  Pandey et al. (2016) offered a literature search for antiinflammatory and immunomodulation citation with ""papaya" and concluded "Although in vitro and in vivo studies have shown that papaya extracts and papaya-associated phytochemicals possess anti-inflammatory and immunomodulatory properties, clinical studies are lacking."  Did not see that they addressed dengue as implied above.  Norhamad et al. 2019 saw change in cytokine level -with papaya leaf extract fed infected mice, did not see a reported therapeutic benefit. observed in the paper

Papaya extracts may have anti-inflammatory and immunomodulation efficacy - that does not translate to cure of viral disease - esp. coronavirus for which there re no data.

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"Papaya extracts may have anti-inflammatory and immunomodulation efficacy - that does not translate to cure of viral disease - esp. coronavirus for which there re no data."

Of course there is no data because covid 19 is a novel virus but we do believe it can reduce Cytokine Storm in the covid 19 infection as the end result of viral flu infections by other viruses mostly the same  which is the Cytokine storm. Ref:
The Influenza a Virus Subtypes H1N1, H1N2 and H3N2 ,HDFx: A Novel Immunomodulator and Potential Fighter Against Cytokine Storms in Viral Flu Infections- Carica Papaya Linn "https://doi.org/10.25141/2472-102X-2017-8.0162

These qualities  reduces Cytokine Storm in other viral flu infections, which can be used as candidate to fight the build up of liquid in the lung due to overwhelm immunity cells production because of the presence of covid 19 virus. If we could reduce the Cytokine storm, we could reduce the chance for a person to develop pneumonia or collapsed lungs and giving the immune system ample time to fight the covid 19 virus.

If people are using HIV drug to test its efficacy in fighting covid 19, why not we try this cheap and easily available compounds to try it on covid 19. I had experienced it myself twice with dengue fever and one with leptospirosis which I managed to survive after few days drinking the crude blended papaya leaves. I had also asked my sister to drink the papaya leaf extract to reduce her asthma and it works, asthma got something to do with the cytokine storm: Ref:
Targeting the "Cytokine Storm" for Therapeutic Benefit DOI: 10.1128/CVI.00636-12 This is how I got the idea to use the papaya leaf extract as candidate to fight covid 19 infection, not directly killing the virus perhaps could prevent its activity that damages the lungs.

It is normal in Malaysia for people to drink papaya leaf juice when they get dengue fever and it works. Of course you need clinical tests for it which would cost lots of money, but there is no harm trying something that might work which could perhaps save many lives when there is no other effective anti-viral drugs or vaccines proven to fight covid 19 so far. We are in race to fight a pandemic that might kill millions of people.

I am collecting data for its effectiveness and if it works, it can save many lives at low cost with easily reached ingredients. Papaya plants grow in Italy nowadays, perhaps it might beneficial to them today. On its toxicology "
'You need to eat 12,000 papaya leaves to get cyanide poisoning' https://www.malaysiakini.com/news/328875
 

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Thanks
 
most recent study, with more patients and published in an non-obscure journal

Sathyapalan, D. T., Padmanabhan, A., Moni, M., P-Prabhu, B., Prasanna, P., Balachandran, S., ... & Jayaprasad, R. (2020). Efficacy & safety of Carica papaya leaf extract (CPLE) in severe thrombocytopenia (≤ 30,000/μl) in adult dengue–Results of a pilot study. PLoS One, 15(2), e0228699.

Abstract

Severe thrombocytopenia in dengue often prompts platelet transfusion primarily to reduce bleeding risk. In India, about 11–43% of dengue patients report receiving platelet transfusions which is considered scarce and expensive especially in resource limited settings. Herein, we evaluated the efficacy and safety of Carica papaya leaf extract (CPLE) in the management of severe thrombocytopenia (≤30,000/μL) in dengue infection. 51 laboratory confirmed adult dengue patients with platelet counts ≤30,000/μL were randomly assigned to either treatment (n = 26) or placebo (n = 24) group. By day 3, CPLE treated patients reported significantly (p = 0.007) increased platelet counts (482%± 284) compared to placebo (331%±370) group. In the treatment group, fewer patients received platelet transfusions (1/26 v/s 2/24) and their median time for platelets to recover to ≥ 50,000/μL was 2 days (IQR 2–3) compared to 3 days (IQR 2–4) in placebo. Overall, CPLE was safe and well tolerated with no significant decrease in mean hospitalization days. Plasma cytokine profiling revealed that by day 3, mean percent increase in TNFα and IFNγ levels in treatment group was less compared to that observed in placebos; (TNFα: 58.6% v/s 127.5%; p = 0.25 and IFNγ: 1.93% v/s 62.6% for; p = 0.12). While a mean percent increase in IL-6 levels occurred in placebos (15.92%±29.93%) by day 3, a decrease was noted in CPLE group (12.95%±21.75%; p = 0.0232). Inversely, CPLE treated patients reported a mean percent increase compared to placebo by day 3 (143% ±115.7% v/s 12.03%± 48.4%; p = 0.006). Further, by day 3, a faster clearance kinetics of viral NS1 antigenemia occurred–mean NS1 titers in treatment group decreased to 97.3% compared to 88% in placebos (p = 0.023). This study demonstrates safety and efficacy of CPLE in increasing platelet counts in severe thrombocytopenia in dengue infections. A possible immunomodulatory and antiviral activity may be attributed to CPLE treatment. These findings merit validation in larger prospective studies.

Trial registration

Name of the registry: Clinical Trials Registry—India (CTRI)

Registration No.: CTRI-REF/2017/02/013314

 

regarding Covid-19

see last statement

"Consumption of papain leaf extract can probably help in fighting Covid-19 infection, but more studies are needed to support this premise. An important step for a start is the in silico docking behavior of potential ligands from papaya leaves extract to the papain-like Covid-19 protease; one of the main targets of Covid-19 antiviral drug screening strategy (Arya et al. 2020; Zhang et al. 2020).

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More Clinical studies of papaya leaf extract effectiveness combating dengue fever. Ref: Institute for Medical Research, Ministry of Health Malaysia.

Publication Details
Year :

2013

Journal :

Soobitha Subenthiran, Tan Chwee Choon, Kee Chee Cheong, Ravindran Thayan, Mok Boon Teck, Prem Kumar Muniandy, Adlin Afzan, Noor Rain Abdullah and Zakiah Ismail (2013). Carica papaya leaves juice significantly accelerates the rate of increase in platelet count among patients with dengue fever and dengue haemorrhagic fever. Evidance-Based Complementary and Alternative Medicine Volume 2013: 7 pages

Abstract :

The study was conducted to investigate the platelet increasing property of Carica papaya leaves juice (CPLJ) in patients with dengue fever (DF). An open labeled randomized controlled trial was carried out on 228 patients with DF and dengue haemorrhagic fever (DHF). Approximately half the patients received the juice, for 3 consecutive days while the others remained as controls and received the standard management. Their full blood count was monitored 8 hours for 48 hours. Gene expression studies were conducted on the ALOX 12 and PTAFR genes. The mean increase in platelet counts were compared in both groups using repeated measure ANCOVA. There was a significant increase in mean platelet count observed in the intervention group (P < 0.001) but not in the control group 40 hours since the first dose of CPLJ. Comparison of mean platelet count between intervention and control group showed that mean platelet count in intervention group was significantly higher than control group after 40 and 48 hours of admission (P < 0.01). The ALOX 12 (FC  =  15.00) and PTAFR (FC  =  13.42) genes were highly expressed among those on the juice. It was concluded that CPLJ does significantly increase the platelet count in patients with DF and DHF.

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15 hours ago, stangerzv said:

If people are using HIV drug to test its efficacy in fighting covid 19, why not we try this cheap and easily available compounds to try it on covid 19. 

!

Moderator Note

Discussion of promising studies is well within our scope as a science forum, but we DO NOT ALLOW posts offering medical advice here. Please STOP making any recommendations regarding what any individual should or shouldn't do with regard to their healthcare (especially concerning medication), or the thread will be closed.

 

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Thanks Phi

A significant but trivial change in platelet count (treatment v control) was observed but was not shown to be clinically relevant.    As authors noted - There is still no specific treatment for dengue.  This publication does not appear to support your excitement for papaya juice.  What in this study did you see as compelling?

Methods are so poorly described that it would be impossible to precisely reproduce this study without contacting authors for more information.  We don;t know papaya juice dosing parameters or how platelet were counted. 

1) Dosing and relevant testing were not made clear.  " Patients in the intervention group received fresh juice from 50 grams of C. papaya leaves, once daily, 15 minutes after breakfast for 3 consecutive days."  I guess we can assume intervention group subjects drank the juice but we do not know when 48 hours of blood testing was initiated relative to consumption.

2) The critical parameter evaluated was platelet count and NO method was identified for this analysis.  Only "The haematological and biochemical tests were conducted by the Pathology Department at Hospital Tengku Ampuan Rahimah, Klang and the validated results were later traced and recorded."

MORE Importantly - Results are not compelling

1) Authors noted "Study on the treatment effect of CPLJ on platelet count regardless of time did not show any significant difference in mean platelet count between intervention and control group."  However, if they dissect time point they did find what in effect was a trivial difference.  " However, analysis of the effect of CPLJ over the study period (time and treatment effect) showed that there was a significant interaction between treatment groups and time."

2) . Normal platelet counts are 150,00-450,000 per microliter.  This report refers to platelet counts but offers no number per any volume.    Fig. 1 reports platelet counts as a simple  number  (no volume identified) difference of treatment v. control.   There was  trivial difference between 1 hour and 40/48 hour time points although authors managed to find a significance in comparison of 0 and 40/48 hour v control.  Look at Fig 1 -  1 hour is really not that much different than 40 and 48 whatever its  statistical difference. 

 

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Hello everybody!

A new study is available on medrxiv prior to peer-review and publication
https://www.medrxiv.org/content/10.1101/2020.03.09.20033217v2.full.pdf
it tells that Covid-19 "lives" shorter on a surface of copper than of stainless steel, cardboard or polymer. Silver was not tested.

A friend of mines proposes and will try to cover doorknobs with copper tape in collective houses. If the quite thin copper foil doesn't hurt the hand, this seems a good idea.
https://en.wikipedia.org/wiki/Copper_tape

I suppose the intricate shape takes narrow tape to cover, where individual layers are loose but two overlapping layers cover the knob completely. The copper tape would end where hands don't touch if possible, and be covered by usual adhesive tape there.

All retail is closed here, but copper tape exists at Web sellers, as long as deliveries work.

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Brass and silver inhibit microorganisms too. Stainless steel and aluminium are the opposite.

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I didn't know that it works for viruses too. Anyone knows the mechanism?

(Then again, I know that silver kills werewolves.)

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1 hour ago, Danijel Gorupec said:

didn't know that it works for viruses too. Anyone knows the mechanism?

There are a few hypotheses and studies on the mechanisms, but no super obvious answers yet. Some studies suggest that radical development (as with many other metals) may be a feature, but the slow rate in the absence of active metabolism (and in dry systems) has made some question the likelihood for viral killing. One common observation is that the genetic material seems to degrade over time.  Some suspect that released copper ions result in oxidizing reactions with proteins which ultimately also affect DNA stability and there are a couple of others around. But as a whole it has been pretty well established that contact killing by copper is a reproducible effect and that it is also typically dose-dependent.

There are also studies showing viral reduction on steel, but the reduction is usually slower than on copper (with some bacteria results are similar).

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Posted (edited)

Please read the protocol  and results as well as the conclusions.   Published or not, it has some flaws.  As can be seen with the top graphs, inconsistent challenge inoculum titers and more importantly LOD's biased (by about a log) in favor of copper treatment.   If cardboard had the same LOD, it would appear nearly as effective as copper.

Edited by PhilGeis

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39 minutes ago, PhilGeis said:

Please read the protocol  and results as well as the conclusions.   Published or not, it has some flaws.  As can be seen with the top graphs, inconsistent challenge inoculum titers and more importantly LOD's biased (by about a log) in favor of copper treatment.   If cardboard had the same LOD, it would appear nearly as effective as copper.

I have not looked at the particular paper, but there have been quite a few over the last decade (especially on norovirus, I believe) that support antibacterial as well as antiviral effects. It is at least plausible that it also applies to coronaviruses (though probably more info is needed).

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Posted (edited)

Yes CharonY - was referring to this paper it's authors fulfilled their expectation based on prev data such as you mentioned.

 

Edited by PhilGeis

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6 hours ago, Enthalpy said:

A friend of mines proposes and will try to cover doorknobs with copper tape in collective houses.

I suggest gloves made of copper/silver/gold wires for a start. Also having UV light (preferably with solar panels) at home for disinfectation is a good idea.

6 hours ago, StringJunky said:

Brass and silver inhibit microorganisms too. Stainless steel and aluminium are the opposite.

A list of metals with biocidal effect is available here:

https://en.m.wikipedia.org/wiki/Oligodynamic_effect

"The metals react with thiol (-SH) or amine (-NH(1,2,3)) groups of proteins, a mode of action to which microorganisms may develop resistance. Such resistance may be transmitted by plasmids.[2]"

 

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22 minutes ago, PhilGeis said:

Yes CharonY - was referring to this paper it's authors fulfilled their expectation based on prev data such as you mentioned.

 

That makes perfect sense, cheers.

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I am just reading a new paper that tries to provide a better measure of COVID-19 associated symptomatic case fatality risk. The result was lower (1.4%) than crude case fatality calculations (4.5%).

 

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16 hours ago, Sensei said:

I suggest gloves made of copper/silver/gold wires for a start. Also having UV light (preferably with solar panels) at home for disinfectation is a good idea.

A list of metals with biocidal effect is available here:

https://en.m.wikipedia.org/wiki/Oligodynamic_effect

"The metals react with thiol (-SH) or amine (-NH(1,2,3)) groups of proteins, a mode of action to which microorganisms may develop resistance. Such resistance may be transmitted by plasmids.[2]"

 

When I see a list with lead, arsenic and mercury on it, I don't immediately think they would be good for me.

There are lots of things that wreck proteins- thos metals and bleach are good examples.

I don't plan to drink bleach as an antiviral.

I'm made of proteins too.

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Hi everybody!

As I read many people using hypochlorite ("bleach") as a disinfectant against Covid-19, I should like to remind that hypochlorite is dangerous. It's the one chemical that kills most people in household accidents.

Percarbonate is a disinfectant too, bur not treacherous like hypochlorite. Where I live, it is sold as 0.5kg powder buckets. Odours and tensides are often added, alas.

Use it dilute in water or as a watery paste to disinfect items suspect of contamination.

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This link goes to Dr Stephanie Seneff Senior Professor MIT

When the surgeons came to us and said they were loosing my daughter to a pneumonia nothing would touch, it was a sulfur drug that brought her out  she was in ICU  Dr seneff’s research has shown exactly what was happening  A friend of my daughter who was in last year of medical school called and gave us the name of pneumonia and med, the pulmonary doctor said no way but we reminded him he said he was loosing her  she came out but then it took weeks before they gave her glycans as she woke up   Anyway if the elderly are on statins which block the liver from process of sulfates I don’t think they will see same results  

https://people.csail.mit.edu/seneff/

The drugs Trump mentioned are too sulfur based  

 

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Do you mean the sulfa drugs?
A rather old group of anti bacterials?

They are useful in some cases, but they are no use against a virus.

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